Faculty Collaboration Database

Novel <i>DNM1L</i> variants impair mitochondrial dynamics through divergent mechanisms. Life Sci Alliance 2022 Aug 01;5(12)

Date

08/02/2022

Pubmed ID

35914810

Pubmed Central ID

PMC9354038

DOI

10.26508/lsa.202101284

Scopus ID

2-s2.0-85135355811 (requires institutional sign-in at Scopus site)   9 Citations

Abstract

Imbalances in mitochondrial and peroxisomal dynamics are associated with a spectrum of human neurological disorders. Mitochondrial and peroxisomal fission both involve dynamin-related protein 1 (DRP1) oligomerisation and membrane constriction, although the precise biophysical mechanisms by which distinct DRP1 variants affect the assembly and activity of different DRP1 domains remains largely unexplored. We analysed four unreported de novo heterozygous variants in the dynamin-1-like gene <i>DNM1L</i>, affecting different highly conserved DRP1 domains, leading to developmental delay, seizures, hypotonia, and/or rare cardiac complications in infancy. Single-nucleotide DRP1 stalk domain variants were found to correlate with more severe clinical phenotypes, with in vitro recombinant human DRP1 mutants demonstrating greater impairments in protein oligomerisation, DRP1-peroxisomal recruitment, and both mitochondrial and peroxisomal hyperfusion compared to GTPase or GTPase-effector domain variants. Importantly, we identified a novel mechanism of pathogenesis, where a p.Arg710Gly variant uncouples DRP1 assembly from assembly-stimulated GTP hydrolysis, providing mechanistic insight into how assembly-state information is transmitted to the GTPase domain. Together, these data reveal that discrete, pathological <i>DNM1L</i> variants impair mitochondrial network maintenance by divergent mechanisms.

Author List

Nolden KA, Egner JM, Collier JJ, Russell OM, Alston CL, Harwig MC, Widlansky ME, Sasorith S, Barbosa IA, Douglas AG, Baptista J, Walker M, Donnelly DE, Morris AA, Tan HJ, Kurian MA, Gorman K, Mordekar S, Deshpande C, Samanta R, McFarland R, Hill RB, Taylor RW, Oláhová M

Authors

Megan C. Harwig Research Scientist II in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin
Michael E. Widlansky MD Associate Director, Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Dynamins
GTP Phosphohydrolases
Humans
Microtubule-Associated Proteins
Mitochondria
Mitochondrial Dynamics
Mitochondrial Proteins